Human Developmental Disorders Research Articles

Mechanisms of RET mediated signal transduction.

The RET receptor tyrosine kinase is physiologically stimulated by growth factors belonging to the glial cell line-derived neurotrophic factor (GDNF) family (GFLs) and by the growth differentiation factor-15 (GDF15) cytokine. RET plays a critical role in normal development as well as in various human tumors and developmental disorders. This review focuses on mechanisms of RET signaling and their alterations in human diseases.

Circular RNA: The evolving potential in the disease world

Circular RNAs (circRNAs), a new star of noncoding RNAs, are a group of endogenous RNAs that form a covalently closed circle and occur widely in the mammalian genome. Most circRNAs are conserved throughout species and frequently show stage-specific expression during various stages of tissue development. CircRNAs were a mystery discovery, as they were initially believed to be a product of splicing errors; however, subsequent research has shown that circRNAs can perform various functions and help in the regulation of splicing and transcription, including playing a role as microRNA (miRNA) sponges. With the application of high throughput next-generation technologies, circRNA hotspots were discovered. There are emerging indications that explain the association of circRNAs with human diseases, like cancers, developmental disorders, and inflammation, and circRNAs may be a new potential biomarker for the diagnosis and treatment outcome of various diseases, including cancer. After the discoveries of miRNAs and long noncoding RNAs, circRNAs are now acting as a novel research entity of interest in the field of RNA disease biology. In this review, we aim to focus on major updates on the biogeny and metabolism of circRNAs, along with their possible/established roles in major human diseases.

Loss of Diphthamide Increases DNA Replication Stress in Mammalian Cells by Modulating the Translation of RRM1.

Diphthamide (DPH) is a highly conserved post-translational modification exclusively present in eukaryotic translation elongation factor 2 (eEF2), with its loss leading to embryonic lethality in mice and developmental disorders in humans. In this study, we unveil the role of diphthamide in mammalian cell DNA damage stress, with a particular emphasis on DNA replication stress. We developed a systematic strategy to identify human proteins affected by diphthamide with a combination of computational profiling and quantitative proteomics. Through this approach, we determine that the translation of RRM1 is modulated by diphthamide via -1 frameshifting. Importantly, our results reveal that the dysregulation of RRM1 translation in DPH-deficient cells is causally linked to elevated DNA replication stress. These findings provide a potential explanation for how diphthamide deficiency leads to cancer and developmental defects in humans.

Mll4 regulates postnatal palate growth and midpalatal suture development.

MLL4, also known as KMT2D, is a histone methyltransferase that acts as an important epigenetic regulator during various organogenesis programs. Mutations in the MLL4 gene are the major cause for Kabuki syndrome, a human developmental disorder that involves craniofacial birth defects, including anomalies in the palate. The purpose of this study was to investigate the role of Mll4 and the underlying mechanisms in the development and growth of the palate. We generated a novel conditional knockout (cKO) mouse model with tissue-specific deletion of Mll4 in the palatal mesenchyme. By using micro-computed tomography (CT), histology, cell mechanism assays, and gene expression analysis approaches, we examined the development and growth of the palate in the Mll4 -cKO mice. Gross intra-oral examination at adult stages showed that Mll4 -cKO mice had defects along the midline of the palate, which included disrupted rugae pattern and widened midpalatal suture. Micro-CT-based skeletal analysis in the adult mice revealed that the overall palate width was decreased in the Mll4 -cKO mice. By using whole-mount and histological staining approaches at perinatal stages, we identified that the midline defects started to appear as early as 1 day prior to birth, manifesting initially as a widened midpalatal suture, accompanied by increased cell apoptosis in the suture mesenchyme cells. Genome-wide analysis of mRNA expression in the midpalatal suture tissue showed that Mll4 is essential for timely expression of major genes for cartilage development, such as Col2a1 and Acan , at birth. These results were validated through immunofluorescence staining, confirming that the expression of chondrogenic markers Sox9 and Col2a1 were markedly decreased, whereas that of the osteogenic marker Runx2 remained unchanged, in the midpalatal suture of the Mll4 -cKO mice. Indeed, time-course histological analysis during postnatal palate growth revealed retardation in the development of the suture cartilage in the Mll4 -cKO mice. In parallel, time-course micro-CT analysis during postnatal palatogenesis confirmed a transverse growth deficit in the palate of the Mll4 -cKO mice. Taken together, our results show that Mll4 is essential for timely occurrence of key cellular and molecular events that lead to proper midpalatal suture development and palate growth.

Cohesin composition and dosage independently affect early development in zebrafish.

Cohesin, a chromatin-associated protein complex with four core subunits (Smc1a, Smc3, Rad21 and either Stag1 or 2), has a central role in cell proliferation and gene expression in metazoans. Human developmental disorders termed 'cohesinopathies' are characterized by germline variants of cohesin or its regulators that do not entirely eliminate cohesin function. However, it is not clear whether mutations in individual cohesin subunits have independent developmental consequences. Here, we show that zebrafish rad21 or stag2b mutants independently influence embryonic tailbud development. Both mutants have altered mesoderm induction, but only homozygous or heterozygous rad21 mutation affects cell cycle gene expression. stag2b mutants have narrower notochords and reduced Wnt signaling in neuromesodermal progenitors as revealed by single-cell RNA sequencing. Stimulation of Wnt signaling rescues transcription and morphology in stag2b, but not rad21, mutants. Our results suggest that mutations altering the quantity versus composition of cohesin have independent developmental consequences, with implications for the understanding and management of cohesinopathies.

Replication properties of a contemporary Zika virus from West Africa.

Zika virus (ZIKV) has become a global health problem over the past decade due to the extension of the geographic distribution of the Asian/American genotype. Recent epidemics of Asian/American ZIKV have been associated with developmental disorders in humans. There is mounting evidence that African ZIKV may be associated with increased fetal pathogenicity necessitating to pay a greater attention towards currently circulating viral strains in sub-Saharan Africa. Here, we generated an infectious molecular clone GUINEA-18 of a recently transmitted human ZIKV isolate from West Africa, ZIKV-15555. The available infectious molecular clone MR766MC of historical African ZIKV strain MR766-NIID was used for a molecular clone-based comparative study. Viral clones GUINEA-18 and MR766MC were compared for their ability to replicate in VeroE6, A549 and HCM3 cell lines. There was a lower replication rate for GUINEA-18 associated with weaker cytotoxicity and reduced innate immune system activation compared with MR766MC. Analysis of chimeric viruses between viral clones stressed the importance of NS1 to NS4B proteins, with a particular focus of NS4B on GUINEA-18 replicative properties. ZIKV has developed strategies to prevent cytoplasmic stress granule formation which occurs in response to virus infection. GUINEA-18 was greatly efficient in inhibiting stress granule assembly in A549 cells subjected to a physiological stressor, with NS1 to NS4B proteins also being critical in this process. The impact of these GUINEA-18 proteins on viral replicative abilities and host-cell responses to viral infection raises the question of the role of nonstructural proteins in the pathogenicity of currently circulating ZIKV in sub-Saharan Africa.

Emergence of the ZNF675 Gene During Primate Evolution-Influenced Human Neurodevelopment Through Changing HES1 Autoregulation.

In this study, we investigated recurrent copy number variations (CNVs) in the 19p12 locus, which are associated with neurodevelopmental disorders. The two genes in this locus, ZNF675 and ZNF681, arose via gene duplication in primates, and their presence in several pathological CNVs in the human population suggests that either or both of these genes are required for normal human brain development. ZNF675 and ZNF681 are members of the Krüppel-associated box zinc finger (KZNF) protein family, a class of transcriptional repressors important for epigenetic silencing of specific genomic regions. About 170 primate-specific KZNFs are present in the human genome. Although KZNFs are primarily associated with repressing retrotransposon-derived DNA, evidence is emerging that they can be co-opted for other gene regulatory processes. We show that genetic deletion of ZNF675 causes developmental defects in cortical organoids, and our data suggest that part of the observed neurodevelopmental phenotype is mediated by a gene regulatory role of ZNF675 on the promoter of the neurodevelopmental gene Hes family BHLH transcription factor 1 (HES1). We also find evidence for the recently evolved regulation of genes involved in neurological disorders, microcephalin 1 and sestrin 3. We show that ZNF675 interferes with HES1 auto-inhibition, a process essential for the maintenance of neural progenitors. As a striking example of how some KZNFs have integrated into preexisting gene expression networks, these findings suggest the emergence of ZNF675 has caused a change in the balance of HES1 autoregulation. The association of ZNF675 CNV with human developmental disorders and ZNF675-mediated regulation of neurodevelopmental genes suggests that it evolved into an important factor for human brain development.

Congenital brain malformations

Malformations of the central nervous system belong to the most common developmental disorders in humans. The clinical presentation of brain malformations is nonspecific including developmental delay, hypotonia, and/or epilepsy. The great heterogeneity concerning etiology, mechanisms of development and morphology is challenging for diagnosis and classification of brain malformations. Thereby recognizing specific malformations is essential for optimal patient management and prognostic evaluation. The aim of this article is to give an overview of several clinically relevant brain malformations occurring from different disrupted developmental processes in brain formation. Several brain malformations are already diagnosed during routine ultrasound in pregnancy. However pre- and postnatal magnetic resonance imaging remains the gold standard in detecting the partially subtle changes and to classify the malformations. Advances in pre- and postnatal neuroimaging techniques and increasing investigation of genetic mechanisms underlying brain formation and its abnormalities have led to abetter understanding of embryologic development and pathogeneses of brain malformations. Besides patient's history and clinical phenotype, neuroimaging plays akey role in diagnosis. Not always aspecific diagnosis can be made, but neuroimaging patterns often enable afocused genetic testing and therefore are revolutionary for etiologic and prognostic assignment. Basic knowledge of brain development facilitates understanding and classifying of structural brain abnormalities.

1H, 13C, and 15N resonance assignments and solution structure of the N-terminal divergent calponin homology (NN-CH) domain of human intraflagellar transport protein 54.

The intraflagellar transport (IFT) machinery plays a crucial role in the bidirectional trafficking of components necessary for ciliary signaling, such as the Hedgehog, Wnt/PCR, and cAMP/PKA systems. Defects in some components of the IFT machinery cause dysfunction, leading to a wide range of human diseases and developmental disorders termed ciliopathies, such as nephronophthisis. The IFT machinery comprises three sub-complexes: BBsome, IFT-A, and IFT-B. The IFT protein 54 (IFT54) is an important component of the IFT-B sub-complex. In anterograde movement, IFT54 binds to active kinesin-II, walking along the cilia microtubule axoneme and carrying the dynein-2 complex in an inactive state, which works for retrograde movement. Several mutations in IFT54 are known to cause Senior-Loken syndrome, a ciliopathy. IFT54 possesses a divergent Calponin Homology (CH) domain termed as NN-CH domain at its N-terminus. However, several aspects of the function of the NN-CH domain of IFT54 are still obscure. Here, we report the 1H, 15N, and 13C resonance assignments of the NN-CH domain of human IFT54 and its solution structure. The NN-CH domain of human IFT54 adopts essentially the α1-α2-α3-α4-α5 topology as that of mouse IFT54, whose structure was determined by X-ray crystallographic study. The structural information and assignments obtained in this study shed light on the molecular function of the NN-CH domain in IFT54.

Epigenetic upregulation of MNAT1 by SMYD2 is linked to PI3K/AKT activation and tumorigenesis of pancreatic adenocarcinoma.

Dysregulation of histone methyltransferase SET and MYND domain-containing protein 2 (SMYD2) has been correlated with human developmental disorders and cancers. This research aims to investigate the roles of SMYD2 and its interacted molecules in pancreatic adenocarcinoma (PAAD). Two PAAD-related gene expression datasets were downloaded to screen key molecules involved in tumor progression. SMYD2 was expressed at high levels in PAAD tissues and cells. SMYD2 silencing suppressed while its overexpression promoted proliferation, invasiveness, migration, apoptosis resistance, and cell cycle progression of PAAD cells. Target molecules of SMYD2 were predicted by online tools and validated by chromatin immunoprecipitation and luciferase assays. SMYD2 catalyzed H3K36me2 modification at the promoter region of MNAT1 component of CDK activating kinase (MNAT1), to promote its transcription. MNAT1 was correlated with an unfavorable clinical outcome of PAAD patients. Alteration of MNAT1 alone also affected the malignant behavior of PAAD cells. Moreover, MNAT1 overexpression in cells rescued the malignant phenotype of cells suppressed by SMYD2 silencing. MNAT1 activated the phosphatidyl inositol 3-kinase/protein kinase B (PI3K/AKT) signaling. In vivo, SMYD2 silencing decreased the growth rate and weight of xenograft tumors in nude mice. Overall, this paper demonstrates that SMYD2-mediated MNAT1 upregulation is linked to PAAD tumorigenesis via PI3K/AKT pathway activation.

Chromatinopathies: insight in clinical aspects and underlying epigenetic changes.

Chromatinopathies (CPs), a group of rare inborn defects characterized by chromatin state imbalance, have evolved from initially resembling Cornelia de Lange syndrome to encompass a wide array of genetic diseases with diverse clinical presentations. The CPs classification now includes human developmental disorders caused by germline mutations in epigenes, genes that regulate the epigenome. Recent advances in next-generation sequencing have enabled the association of 154 epigenes with CPs, revealing distinctive DNA methylation patterns known as episignatures.It has been shown that episignatures are unique for a particular CP or share similarities among specific CP subgroup. Consequently, these episignatures have emerged as promising biomarkers for diagnosing and treating CPs, differentiating subtypes, evaluating variants of unknown significance, and facilitating targeted therapies tailored to the underlying epigenetic dysregulation.The following review was conducted to collect, summarize, and analyze data regarding CPs in such aspects as clinical evaluation encompassing long-term patient care, underlying epigenetic changes, and innovative molecular and bioinformatic methodologies that have been devised for the assessment of CPs. We have also shed light on promising novel treatment options that have surfaced in recent research and presented a synthesis of ongoing clinical trials, contributing to the current understanding of the dynamic and evolving nature of CPs investigation.

Children with Rare Nager Syndrome-Literature Review, Clinical and Physiotherapeutic Management.

Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb deformities, mandibular hypoplasia, hypoplasia or absence of thumbs, microretrognathia, and ankylosis of the temporomandibular joint. The prevalence is very rare and the literature describes only about a hundred cases of Nager syndrome. There is evidence of autosomal dominant and autosomal recessive inheritance for Nager syndrome, suggesting genetic heterogeneity. The majority of the described causes of Nager syndrome include pathogenic variants in the SF3B4 gene, which encodes a component of the spliceosome; therefore, the syndrome belongs to the spliceosomopathy group of diseases. The diagnosis is made on the basis of physical and radiological examination and detection of mutations in the SF3B4 gene. Due to the diversity of defects associated with Nager syndrome, patients require multidisciplinary, complex, and long-lasting treatment. Usually, it starts from birth until the age of twenty years. The surgical procedures vary over a patient's lifetime and are related to the needed function. First, breathing and feeding must be facilitated; then, oral and facial clefts should be addressed, followed by correcting eyelid deformities and cheekbone reconstruction. In later age, a surgery of the nose and external ear is performed. Speech and hearing disorders require specialized logopedic treatment. A defect of the thumb is treated by transplanting a tendon and muscle or transferring the position of the index finger. In addition to surgery, in order to maximize a patient's benefit and to reduce functional insufficiency, complementary treatments such as rehabilitation and physiotherapy are recommended. In our study, we describe eight patients of different ages with various cases of Nager syndrome. The aim of our work was to present the actual genetic knowledge on this disease and its treatment procedures.

Effect of Demethylation on the Presence of DNA Methyltransferases in Complex with Histone Methylation Markers in Two Myeloma Cell Lines

Background: Enzymes that catalyze CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B) are also implicated in human developmental disorders and cancers, supporting the critical role of DNA methylation. Posttranslational modifications of histones influence the representation of DNMTs in protein complexes including specific histone markers. H3K4me3, H3K36me3 are histone markers of active gene transcription, while for example H3K9me3, H3K27me3 are histone markers of inactive chromatin associated with repressive transcription of the respective genes. Objective: The aim of the study was to find whether demethylation of myeloma cells can affect 1) the formation of a complex of the repressive histone marker - H3K9me3 with DNMT3A and/or DNMT3B; and 2) association of the transcriptionally active histone marker H3K4me3 with DNMT1. Material & Methods: Chromatin lysate was isolated from two myeloma cell lines - KMS12-BM and KMS12-PE, after their 72 hours treatment with 5-Azacytidine (AZA) and/or 5-Aza-2´-deoxycitidine (DAC). Precipitation was performed with antibodies against H3K9me3 and/or H3K4me3. The occurrence of DNMT3A and/or DNMT3B in precipitated complex with H3K9me3 was quantified by qPCR (SYBR Green I) with primers specific for both promoter or coding regions of the respective DNMT genes. The assesment of DNMT1 in complex precipitated with H3K4me3 was quantified by qPCR (SYBR Green I) with primers specific for DNMT1. For result calculation, the 2-delta Ct values of immunoprecipitated samples were normalized to the 2-delta Ct value of IgG respective antibodies, and then the obtained 2(-(delta delta Ct)) value of analyzed samples was normalized to the 2(-(delta delta Ct)) value of control untreated cells (DMSO). Results: In KMS12-PE myeloma cells, we determined the 2(-(delta delta Ct)) values of DNMT3B in precipitated complex with H3K9me3 - 1.52 and 1.47, in cells treated with 0.5 µM AZA and 0.5 µM DAC, respectively. The obtained 2(-(delta delta Ct) values were higher than that of control untreated (DMSO) myeloma cells [with the of 2(-(delta delta Ct)) value of 0.85]. Increased occurrence of DNMT3A was found in H3K9me3 complex of all analyzed samples in comparison to untreated control cells [with the of 2(-(delta delta Ct)) value of 0.89]; the highest 2(-(delta delta Ct) values - 1.07 and 1.21 were determined after DAC treatment. The obtained 2(-(delta delta Ct)) values of DNMT1 from analyzed precipitated samples with H3K4me3 were lower than that of DMSO treated KMS12-PE cells [with the of 2(-(delta delta Ct)) value of 0.85]. In KMS12-BM, we did not detect any changes in the abundance of DNMT3B in precipitated complexes including H3K4me3. Conclusion: In KMS12-PE, but not in KMS12-BM, both demethylation agents used, 5-Aza-2´-deoxycitidine and 5-Azacytidine, affected the appearance of DNMT3A and DNMT3B in a protein complex containing the repressive histone marker H3K9me3 with possible potential to inactivate gene transcription.

Brain organoids: A revolutionary tool for modeling neurological disorders and development of therapeutics.

Brain organoids are self-organized, three-dimensional (3D) aggregates derived from pluripotent stem cells that have cell types and cellular architectures resembling those of the developing human brain. The current understanding of human brain developmental processes and neurological disorders has advanced significantly with the introduction of this in vitro model. Brain organoids serve as a translational link between two-dimensional (2D) cultures and in vivo models which imitate the neural tube formation at the early and late stages and the differentiation of neuroepithelium with whole-brain regionalization. In addition, the generation of region-specific brain organoids made it possible to investigate the pathogenic and etiological aspects of acquired and inherited brain disease along with drug discovery and drug toxicity testing. In this review article, we first summarize an overview of the existing methods and platforms used for generating brain organoids and their limitations and then discuss the recent advancement in brain organoid technology. In addition, we discuss how brain organoids have been used to model aspects of neurodevelopmental and neurodegenerative diseases, including autism spectrum disorder (ASD), Rett syndrome, Zika virus-related microcephaly, Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).

Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies

Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L variants, functional studies were performed in Drosophila and human cells. The fruit fly DOT1L ortholog, grappa, is expressed in most cells including neurons in the central nervous system. The identified DOT1L variants behave as gain-of-function alleles in flies and lead to increased H3K79 methylation levels in flies and human cells. Our results show that human DOT1L and fly grappa are required for proper development and that de novo heterozygous variants in DOT1L are associated with a Mendelian disease.

Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders.

Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub-family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co-ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.

A novel heterozygous truncating variant in the AGO1 gene in an Iranian family with schizophrenia as an unreported symptom.

Intellectual disability (ID) and autism spectrum disorders (ASDs) are the most common developmental disorders in humans. Combined, they affect between 3% and 5% of the population. Although high-throughput genomic methods are rapidly increasing the pool of ASD genes, many cases remain idiopathic. AGO1 is one of the less-known genes related to ID/ASD. This gene encodes a core member protein of the RNA-induced silencing complex, which suppresses mRNA expression through cleavage, degradation, and/or translational repression. Generally, patients with defects in the AGO1 gene manifest varying degrees of ID, speech delay, and autistic behaviors. Herein, we used whole-exome sequencing (WES) to investigate an Iranian family with two affected members one of whom manifested ID and autism and the other showed borderline ID and schizophrenia. WES analysis identified a novel heterozygous truncating variant (NM_012199.5:c.1298G>A, p.Trp433Ter) in the AGO1 gene that co-segregated with the phenotypes using Sanger sequencing. Moreover, the structural analysis showed that due to this variant, two critical domains (Mid and PIWI) of the AGO1 protein have been lost, which has a detrimental effect on the protein's function and structure. To the best of our knowledge, schizophrenia has not been reported in patients with AGO1 deficiency, which is a novel phenotypic finding that expands the AGO1-related behavioral disorders. Moreover, this study's findings determined that patients with the same variant in the AGO1 gene may show heterogeneity in manifested phenotypes.

The Roles of Histone Lysine Methyltransferases in Heart Development and Disease.

Epigenetic marks regulate the transcriptomic landscape by facilitating the structural packing and unwinding of the genome, which is tightly folded inside the nucleus. Lysine-specific histone methylation is one such mark. It plays crucial roles during development, including in cell fate decisions, in tissue patterning, and in regulating cellular metabolic processes. It has also been associated with varying human developmental disorders. Heart disease has been linked to deregulated histone lysine methylation, and lysine-specific methyltransferases (KMTs) are overrepresented, i.e., more numerous than expected by chance, among the genes with variants associated with congenital heart disease. This review outlines the available evidence to support a role for individual KMTs in heart development and/or disease, including genetic associations in patients and supporting cell culture and animal model studies. It concludes with new advances in the field and new opportunities for treatment.

See[ing] elegance in sensory biology: an interview with Piali Sengupta.

See[ing] elegance in sensory biology: an interview with Piali Sengupta.

Rediscovering Primary Cilia in Pancreatic Islets.

Primary cilia are microtubule-based sensory and signaling organelles on the surfaces of most eukaryotic cells. Despite their early description by microscopy studies, islet cilia had not been examined in the functional context until recent decades. In pancreatic islets as in other tissues, primary cilia facilitate crucial developmental and signaling pathways in response to extracellular stimuli. Many human developmental and genetic disorders are associated with ciliary dysfunction, some manifesting as obesity and diabetes. Understanding the basis for metabolic diseases in human ciliopathies has been aided by close examination of cilia action in pancreatic islets at cellular and molecular levels. In this article, we review the evidence for ciliary expression on islet cells, known roles of cilia in pancreas development and islet hormone secretion, and summarize metabolic manifestations of human ciliopathy syndromes. We discuss emerging data on primary cilia regulation of islet cell signaling and the structural basis of cilia-mediated cell crosstalk, and offer our interpretation on the role of cilia in glucose homeostasis and human diseases.